Stress pathway dysregulation is the most pervasive symptom in neuropsychiatric disease. Patients with schizophrenia and autism show heightened stress sensitivity and exacerbated symptoms during stress experience. It has long been postulated that a hyperactive stress system links stress dysregulation to neuropsychiatric disease, which has promoted the pharmaceutical pursuit of therapeutic targets including antagonists of the CRF receptor-1 (CRFR1) that would blunt this response. Utilizing CRF receptor-2 (CRFR2) deficient mice in which disruption of normal stress neurocircuitry prevents the recruitment and promotion of homeostatic mechanisms during stress, we have demonstrated that an inability to adapt to stress has severe consequences, including cell death within the 5-HT producing raphe nucleus, maladaptive physiological and behavioral stress responses, and increased perseverative behaviors. CRFR2-deficient mice showed elevated proinflammatory cytokines and their downstream effectors including proapoptotic caspases, increased markers of microglia infiltration, and a 20-fold increased level of the CRF binding protein (CRF-BP). These alterations likely contribute to the increased cell death and stress-sensitivity phenotype in these mice. Therefore, we hypothesize that cytokine-induced increases in CRF-BP prevent CRF from activating postsynaptic CRFR1, producing a counterintuitive hypoactive response in the raphe and an inhibition of the normal stress-induced 5-HTergic neurotransmission necessary to promote arousal and coping behaviors. PUBLIC HEALTH RELEVANCE: Stress pathway dysregulation is the most pervasive symptom across neuropsychiatric diseases. In a mouse model of stress dysregulation, we have found that CRFR2-deficient mice show elevated proinflammatory cytokines and their downstream effectors including proapoptotic caspases, increased markers of microglia infiltration, and increased levels of the CRF binding protein in the raphe. We hypothesize that neuroinflammatory cytokines and increased CRF binding protein in the raphe prevent CRF from activating postsynaptic CRFR1, producing a counterintuitive hypoactive response and an inhibition of the normal stress- induced 5-HT neurotransmission necessary to promote arousal and coping behaviors.